Weekly semaglutide-insulin combo outperforms daily insulin in type 2 diabetes trial

A once-weekly injection combining semaglutide with the basal insulin icodec controlled blood sugar better than once-daily insulin glargine U100 in adults with type 2 diabetes, according to results from the COMBINE 4 trial published September 10, 2026, in The Lancet Diabetes & Endocrinology ^[1]. The product, called IcoSema and developed by Novo Nordisk, is not approved in the United States ^[1].

COMBINE 4 was a 40-week, multinational, randomized, open-label phase 3b trial. Researchers assigned 243 adults to IcoSema and 242 to glargine U100. Participants had type 2 diabetes and had not previously taken insulin or a GLP-1 receptor agonist. At the start of the study, 87% were taking metformin and about a third were taking SGLT2 inhibitors. More than 90% of people in both groups completed the 40-week treatment period ^[1].

Average A1c fell from 9.57% to 6.22% with IcoSema, compared with a drop from 9.50% to 7.10% with glargine U100. The difference between the groups was 0.88 percentage points, which the researchers reported as superiority (P < .001). Fasting plasma glucose fell by similar amounts in both groups ^[1].

Body weight decreased by an average of 0.79 kg (1.7 lbs) in the IcoSema group, while glargine U100 was linked to an average gain of 3.81 kg (8.4 lbs) (P < .001) ^[1].

Low blood sugar was less frequent with IcoSema. At least one episode of clinically significant hypoglycemia occurred in 9% of IcoSema participants versus 22% of those on glargine U100. Three severe episodes occurred in two people taking IcoSema, compared with six episodes in five people taking glargine. From the start of the study to week 45, combined clinically significant and severe hypoglycemia rates per person-year of exposure were 0.29 with IcoSema and 0.59 with glargine U100 (P = .04) ^[1].

Gastrointestinal side effects were more common with IcoSema — 56% versus 21% — and led to treatment discontinuation in four people taking IcoSema and none taking glargine U100 ^[1].

The trial was open-label, meaning participants and their doctors knew which treatment was being used ^[1]. It was funded by Novo Nordisk. Lead author Linong Ji, MD, of Peking University in Beijing, and colleagues reported research support and consulting fees from several companies, including Novo Nordisk ^[1]. Earlier phase 3a COMBINE 1-3 trials had tested IcoSema against insulin icodec alone, semaglutide alone, and glargine plus mealtime insulin aspart in people whose blood sugar was not controlled on basal insulin alone ^[1].

IcoSema is approved under the brand name Kyinsu in the European Union, China, Japan, South Korea and other countries ^[1]. In the US, insulin icodec was approved by the FDA in March 2026 under the brand name Awiqli for adults with type 2 diabetes ^[1]. Novo Nordisk has not filed an application for IcoSema in the US. A company spokesperson told Medscape Medical News: "We continue to assess the situation and determine whether and when a future filing may be appropriate" ^[1].

Why it matters for patients

IcoSema is designed to deliver semaglutide and insulin icodec in a single weekly injection. The study authors wrote that the findings offer "reassurance regarding concerns around hypoglycaemia and weight gain that may accompany insulin intensification after oral glucose-lowering medications while reducing the injection burden associated with once-daily therapies" ^[1].

The weight results point in opposite directions for the two groups: glargine U100 produced an average gain of more than 8 pounds, while the combination produced a small average loss ^[1]. The trade-off was gastrointestinal side effects, which were reported in 56% of people taking IcoSema compared with 21% taking glargine, and which caused four people on the combination to stop treatment ^[1].

None of this changes what is available in the US right now. IcoSema has not been filed for approval here, so there is no US price, insurance coverage or launch date to report; none has been disclosed ^[1]. The study did not report long-term cardiovascular outcomes, and it has not been reported how the combination compares with basal-bolus insulin regimens for people whose blood sugar is not controlled ^[1].

What happens next

Novo Nordisk has not said whether or when it will seek US approval of IcoSema, and no timeline has been disclosed ^[1]. Insulin icodec on its own, sold as Awiqli, has been available in the US since its March 2026 approval for adults with type 2 diabetes ^[1].